TY - JOUR
T1 - A new missense variant in RAB3GAP2 in a family with muscular dystrophy–short stature and defective autophagy
T2 - An expansion of the micro/Martsolf spectrum or a new phenotype?
AU - Mora-Roldan, German A.
AU - Galaviz-Hernandez, Carlos
AU - Hiebert-Froese, Jose
AU - Hernandez, Arturo
AU - Montes, Luis
AU - Duran-Pasten, Maria L.
AU - Gazarian, Karlen
AU - Zenteno, Juan C.
N1 - Funding Information:
Consejo Nacional de Ciencia y Tecnología, Grant/Award Number: 568454
Publisher Copyright:
© 2022 Wiley Periodicals LLC.
PY - 2022/7
Y1 - 2022/7
N2 - We describe a sibling pair of Mennonite origin born from consanguineous parentage with a likely new phenotype of limb–girdle muscular dystrophy, short stature, ptosis, and tracheomalacia. Exome sequencing in the affected subjects identified a novel homozygous RAB3GAP2 missense variant as the potential causal variant. As RAB3GAP2 has been recently shown to be involved in the autophagy process, we analyzed patient-derived fibroblasts by fluorescence microscopy and demonstrated defective autophagic flux under rapamycin and serum starvation conditions when compared with wild-type cells. The phenotype in the siblings described here is distinct from Martsolf and Warburg's micro syndromes, the currently known diseases arising from RAB3GAP2 pathogenic variants. Thus, this work describes a potentially novel recessive phenotype associated with a RAB3GAP2 defect and manifesting as a muscular dystrophy–short stature disorder with no ocular anomalies. Functional analyses indicated defective autophagy in patient-derived fibroblasts, supporting the involvement of RAB3GAP2 in the etiology of this disorder. Our results contribute to a better characterization of the Martsolf/micro spectrum phenotype.
AB - We describe a sibling pair of Mennonite origin born from consanguineous parentage with a likely new phenotype of limb–girdle muscular dystrophy, short stature, ptosis, and tracheomalacia. Exome sequencing in the affected subjects identified a novel homozygous RAB3GAP2 missense variant as the potential causal variant. As RAB3GAP2 has been recently shown to be involved in the autophagy process, we analyzed patient-derived fibroblasts by fluorescence microscopy and demonstrated defective autophagic flux under rapamycin and serum starvation conditions when compared with wild-type cells. The phenotype in the siblings described here is distinct from Martsolf and Warburg's micro syndromes, the currently known diseases arising from RAB3GAP2 pathogenic variants. Thus, this work describes a potentially novel recessive phenotype associated with a RAB3GAP2 defect and manifesting as a muscular dystrophy–short stature disorder with no ocular anomalies. Functional analyses indicated defective autophagy in patient-derived fibroblasts, supporting the involvement of RAB3GAP2 in the etiology of this disorder. Our results contribute to a better characterization of the Martsolf/micro spectrum phenotype.
KW - RAB3GAP2
KW - autophagy
KW - muscular dystrophy
UR - http://www.scopus.com/inward/record.url?scp=85125993886&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.62723
DO - 10.1002/ajmg.a.62723
M3 - Artículo
C2 - 35274444
AN - SCOPUS:85125993886
SN - 1552-4825
VL - 188
SP - 1972
EP - 1978
JO - American Journal of Medical Genetics
JF - American Journal of Medical Genetics
IS - 7
ER -